PROJECT SUMMARY Treatment of locally advanced head and neck cancer (LAHNC) commonly entails the use of radiation therapy, which often exposes portions of the brain, particularly the cerebellum and inferior temporal lobes, to moderately high doses of radiation. The negative effects of cranial radiation exposure on cognition are well established in other types of malignancies, but remain unstudied in LAHNC patients. The underlying disease process, chemotherapeutic agents, and radiation dose distribution in patients treated for LAHNC are fundamentally different from the patient populations previously studied, suggesting that patterns of cognitive impairment may also differ. This scientific proposal will elucidate the cognitive effects of radiation in LAHNC patients through three specific aims. Scientific Aim 1 will characterize the cognitive profiles of LAHNC survivors by administering a neuropsychological battery and patient questionnaires. Radiation dosimetry to individual regions of the cerebellum and temporal lobes will be calculated from the original treatment plans. The effects of patient and treatment characteristics (including chemotherapy exposure and radiation dosimetry) on post- treatment cognition will be assessed. Scientific Aim 2 will determine the association between cognitive impairment and germline variants. Germline single nucleotide polymorphisms will be determined using a biologically-plausible, carefully curated candidate gene approach and assessed for association with the neurocognitive battery results. Scientific Aim 3 will explore how modern radiation planning techniques can be utilized to reduce brain radiation exposure for LAHNC treatment. Comparison radiation plans will be generated using Multi-Criteria Optimized intensity modulation and proton therapy. This study will promote my long-term career goal of improving quality of life for patients who received radiation therapy and will provide opportunities for additional training and career development. The career development plan includes training in biostatistical and research methodology, normal tissue complication probability modeling, and fundamentals of molecular epidemiology and cognitive assessment. The scientific and training plans are supported by a team of experienced mentors and advisors who are committed to the success of this project and my development as a clinician scientist. The primary mentor is an expert in neurocognitive outcomes among cancer survivors, an experienced mentor of young investigators, and the director of the UAB Institute for Cancer Outcomes and Survivorship. The results of this proposal will be utilized to form the foundation of a future clinical trial designed to reduce cognitive morbidity in LAHNC patients by identifying those patients at highest risk for cognitive impairment, maximally reducing brain radiation exposure, and implementing a tailored cognitive remediation intervention. This project will strengthen my skills as a clinical researcher, establish an independent research platform, and make a true contribution towards improving clinical outcomes in cancer survivors.